Figures
- FIGURE 1
Flow chart of the trial profile. Patients with a positive mannitol test were included. FeNO: exhaled nitric oxide fraction; ACQ: Asthma Control Questionnaire.
- FIGURE 2
Number of participants at each level of inhaled corticosteroid (ICS) treatment at baseline in the exhaled nitric oxide fraction (FeNO) group and Asthma Control Questionnaire (ACQ) group, followed by the number of participants regulated according to the algorithms at visit 2 and 3, and finally the number of participants at each ICS treatment step in the two groups at final visit.
- FIGURE 3
Geometric mean (95% CI) response dose ratio (RDR) at each visit for the two intervention groups. Analyses of difference between groups at each visit are based on Wilcoxon rank sum tests. p-values at visits 2, 3 and 4 were p=0.53, p=0.015 and p=0.62, respectively. FeNO: exhaled nitric oxide fraction; ACQ: Asthma Control Questionnaire.
- FIGURE 4
Median (95% CI) exhaled nitric oxide fraction (FeNO) at each visit for the two intervention groups. Analyses of difference between groups at each visit are based on Wilcoxon rank sum tests. p-values at visits 2, 3 and 4 were p=1.00, p=0.01 and p=0.03, respectively. ACQ: Asthma Control Questionnaire.
Tables
- TABLE 1
Exhaled nitric oxide fraction (FeNO) algorithm
FeNO concentration ppb ICS dose change ACQ score β2-agonist dose change Level 1 >29 ↑ 1 ICS step ≤1.5 No change Level 2 16–29 No change >1.5 ↑ 1 LABA step Level 3 <16 ↓ 1 ICS step NA (FeNO >29 ppb) No change ICS: inhaled corticosteroid; ACQ: Asthma Control Questionnaire; LABA: long-acting β2-agonist; NA: not applicable.
- TABLE 2
Treatment steps for the exhaled nitric oxide fraction algorithm
ICS treatment step# β2-agonist treatment step¶ Step 1: 0 Step 1: terbutalin as required Step 2: budesonide 100 µg twice daily Step 2: formoterol 4.5 µg twice daily Step 3: budesonide 200 µg twice daily Step 3: formoterol 9 µg twice daily Step 4: budesonide 400 µg twice daily Step 4: formoterol 2×9 µg twice daily Step 5: budesonide 800 µg twice daily ICS: inhaled corticosteroid. #: based on exhaled nitric oxide fraction concentration; ¶: based on asthma control questionnaire score.
- TABLE 3
Asthma Control Questionnaire (ACQ) algorithm and treatment steps
ACQ score Treatment adjustment Level 1 >1.5 ↑ 1 step Level 2 0.75–1.5 No change Level 3 <0.75 ↓ 1 step Treatment Step 1 Terbutalin as required Step 2 Budesonide 200 µg twice daily Step 3 Budesonide 400 µg twice daily Step 4 Budesonide 400 µg and formoterol 9 µg twice daily Step 5 Budesonide 800 µg and formoterol 18 µg twice daily - TABLE 4
Participant data at V2 (8 weeks)
ACQ group FeNO group p-value# Subjects n 36 36 Demographic details¶ Mean age years 30 (24–46) 42 (27–52) 0.1 Height cm 172±9 173±8 0.7 Weight kg 71 (62–85) 75 (66–80) 0.5 BMI kg·m−2 24.2 (21.8–26.5) 24.3 (21.7–27.7) 0.7 Atopy 24 (67) 22 (63) 0.7 Smoking 0.3 Current 5 (14) 11 (28) Ex 12 (32) 10 (25) Never 20 (54) 19 (48) Smoking history pack-years 6.0 (0.8–11.0) 10.0 (5.5–18.8) 0.2 Asthma-related QoL ACQ 1.2 (0.2–1.6) 0.8 (0.4–2.0) 0.7 Mini AQLQ 6.1 (5.2–6.5) 6.3 (5.4–6.7) 1.0 Spirometry RDR %·mg−1 0.04 (0.02–0.06) 0.03 (0.02–0.06) 0.5 Mean FEV1 L 3.25±0.86 3.25±0.85 1.0 Mean FEV1 % 92.4±11.3 94.7±16.2 0.5 Mean FVC L 4.17±1.18 4.38±0.89 0.4 Mean FEV1/FVC % 78.8±8.1 73.8±9.4 0.02 FeNO ppb 21 (13–32) 22 (13–31) 1.0 Present treatment ICS use 37 (97) 40 (100) 0.3 ICS dose µg 400 (400–400) 400 (400–400) 0.1 LABA use 6 (15) 5 (13) 0.8 LABA dose µg 9 (9–18) 18 (18–36) 0.1 Inflammatory features Leukocyte ×109·L−1 6.5 (5.3–7.8) 6.5 (5.3–8.1) 0.8 Eosinophil ×109·L−1 0.14 (0.11–0.20) 0.18 (0.10–0.31) 0.5 Neutrophil ×109·L−1 4 (2.7–5.2) 3.3 (3.1–5.1) 0.9 CRP mg·L−1 1.1 (0.6–2.5) 1.0 (1.0–2.7) 0.9 IgE kU·L−1 99 (19–325) 98 (39–259) 1.0 IL-6 pg·mg−1 1.2 (0.8–2.1) 1.5 (1.0–2.2) 0.3 IL-8 pg·mg−1 110 (47–168) 116 (80–180) 0.6 Sputum inflammation Eosinophils % 0.38 (0.25–0.82) 0.88 (0.25–3) 0.1 Neutrophils % 38.0 (21.1–49.1) 28.0 (9.1–68.4) 0.9 Macrophages % 40.8 (17.3–57) 30.6 (18.8–64.3) 0.9 Columnar epithelia % 11.4 (4.4–20.6) 12.1 (5.0–18.3) 0.8 Data are presented as median (interquartile range), mean±sd or n (%), unless otherwise stated. ACQ: Asthma Control Questionnaire; FeNO: exhaled nitric oxide fraction; BMI: body mass index; QoL: quality of life; AQLQ: Asthma Quality of Life Questionnaire; RDR: response dose ratio; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; CRP: C-reactive protein; Ig: immunoglobulin; IL: interleukin. #: based on Chi-squared tests, t-tests and Wilcoxon rank sum tests; ¶: data from 80 subjects (40 in each group).
- TABLE 5
Change in asthma profile from V2 (8 weeks) to V4 (36 weeks)
Unadjusted FeNO group Adjusted FeNO group Adjusted p-value Asthma-related QoL ACQ# −0.2 (−0.7–0.3) −0.1 (−0.6–0.3) 0.5 Mini AQLQ# 0.2 (−0.3–0.6) 0.1 (−0.3–0.6) 0.6 Spirometry RDR %·mg−1#,¶ 0.16 (−0.14–0.46) −0.02 (−0.05–0.02) 0.3 Mean FEV1 L 0.08 (−0.01–0.17) 0.07 (−0.02–0.16) 0.1 Mean FEV1 % 2.5 (−0.3–5.2) 2.3 (−0.5–5.0) 0.1 Mean FVC L# −0.10 (−0.22–0.03) −0.10 (−0.23–0.03) 0.1 Mean FEV1/FVC %# 0.03 (−0.00–0.05) 0.02 (−0.00–0.05) 0.1 FeNO ppb# −17 (−36–2) −13 (−20– −5) 0.001 Present treatment ICS dose µg# −25 (−224–174) 5 (−194–204) 1.0 LABA dose µg# 29 (−105–162) 42 (−121–205) 0.5 Inflammatory features Leukocyte ×109·L−1# −2.8 (−9.4–3.8) −3.1 (−9.8–3.6) 0.4 Eosinophil ×109·L−1# −0.06 (−0.21–0.09) 0 (−0.10–0.11) 0.9 Neutrophil ×109·L−1# −0.2 (−1.2–0.9) −0.2 (−1.1–0.7) 0.6 CRP mg·L−1# −0.7 (−2.5–1.1) −0.7 (−2.2–0.9) 0.4 IgE kU·L−1 34 (−94–161) 12 (−66–91) 0.8 IL-6 pg·mg−1 −0.4 (−1.4–0.5) −0.2 (−0.7–0.3) 0.4 IL-8 pg·mg−1 71.2 (−155.8–298.2) 62.4 (−143.9–268.7) 0.6 Sputum inflammation Eosinophils %# −9.14 (−18.50–0.21) −7.91 (−16.83–1.01) 0.1 Neutrophils % 2.1 (−17.3–21.5) 2.2 (−16.4–20.7) 0.8 Macrophages % 2.1 (−12.9–17.2) 1.2 (−12.3–14.7) 0.9 Columnar epithelia %# 4.9 (−7.9–17.7) 4.8 (−8.1–17.6) 0.5 Data are presented as mean differences (95% CI) based on linear regression analyses, unless otherwise stated. Changes in the Asthma Control Questionnaire (ACQ) group were used as reference. Crude and adjusted analyses were performed for the baseline level of the outcome. FeNO: exhaled nitric oxide fraction; QoL: quality of life; AQLQ: Asthma Quality of Life Questionnaire; RDR: response dose ratio; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; CRP: C-reactive protein; Ig: immunoglobulin; IL: interleukin. #: in cases where the model assumptions were violated the effect estimates were checked with robust linear regression; ¶: analysis of 26 patients in the FeNO group and 28 patients in the ACQ group.
- TABLE 6
Participant asthma profile at V4 (36 weeks)
ACQ group FeNO group p-value# Subjects n 29 29 Quality of life ACQ 0.8 (0.4–2) 0.8 (0.4–1.8) 0.7 Mini AQLQ 6.2 (5.3–6.6) 6.2 (5.3–6.6) 0.5 Spirometry RDR %·mg−1¶ 0.02 (0.01–0.06) 0.02 (0.01–0.06) 0.6 FEV1 L 3.15±0.96 3.33±0.85 0.4 FEV1 % 89.7±12.4 94.6±15.4 0.2 FVC L 4.17±1.22 4.41±0.96 0.4 FEV1/FVC % 75.8±8.1 75.3±8.4 0.8 FeNO ppb 21 (14–29) 15 (12–18) 0.03 Present treatment ICS use 17 (59) 20 (67) 0.5 ICS dose 0 (0–800) 100 (0–600) 0.8 LABA use 8 (28) 11 (37) 0.5 LABA dose 18 (18–18) 18 (9–36) 0.7 Inflammatory features Leukocyte ×109·L−1 6.0 (5.3–8.1) 6.0 (5.3–8.1) 0.4 Eosinophil ×109·L−1 0.14 (0.10–0.27) 0.17 (0.11–0.26) 0.7 Neutrophil ×109·L−1 3.50 (2.70–4.10) 2.90 (2.50–4.30) 0.3 CRP mg·L−1 1.0 (1.0–2.0) 1.0 (1.0–1.4) 0.8 IgE kU·L−1 79 (7–235) 56 (15–211) 0.9 IL-6 pg·mg−1 1.5 (0.9–2.4) 1.3 (0.9–2.1) 0.7 IL-8 pg·mg−1 106.9 (33.0–248.1) 127.7 (61.6–222.3) 0.6 Sputum inflammation Eosinophils % 0.75 (0–3.25) 1.38 (0.25–2.75) 0.7 Neutrophils % 21.8 (11.3–54.5) 25.6 (13.6–65.6) 0.7 Macrophage % 42.8 (12.3–67.0) 35.1 (19.5–58.6) 0.5 Columnar epithelia % 5.5 (1.8–26.5) 15 (5.3–30.3) 0.2 Data are presented as median (interquartile range), mean±sd or n (%), unless otherwise stated. ACQ: Asthma Control Questionnaire; FeNO: exhaled nitric oxide fraction; AQLQ: Asthma Quality of Life Questionnaire; RDR: response dose ratio; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; CRP: C-reactive protein; Ig: immunoglobulin; IL: interleukin. #: based on Chi-squared tests, t-tests and Wilcoxon rank sum tests; ¶: analysis of 26 patients in the FeNO group and 28 patients in the ACQ group.
